Concordance between Wada, Transcranial Magnetic Stimulation, and Magnetoencephalography for Determining Hemispheric Dominance for Language: A Retrospective Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study investigates concordance of TMS, Wada, and MEG in determining brain language dominance in 12 patients having epilepsy/tumor. The study is interesting, but requires further corrections and explanations:

 

Major

-Please elaborate in the Methodology (2.4.1) more profoundly how the synchronization of the presentation of pictures and the stimulus  (TMS) application adjusted. Did the authors use external presentation software to trigger the onset of TMS stimulation? What is the TMS stimulation given at the zero time with the picture onset?

-How TMS mapping was standardized per subject, please explain the protocol in language mapping with respect to the brain areas.

-Elaborate more profoundly on the language tests used in the study for all three methods (TMS, MEG, and Wada) with placing references. Detailed information is missing, for example, how many pictures were finally taken for each subject for mapping, etc.

-In Table 1 of the Results the column “Handedness” states on the hand dominance. Could authors state how the handedness was tested (Edinburgh?), there is no explanation in the Methodology. Please update this information in the Methodology section (and updating also Table 1 for clarification) with the required references.

In the raw 253 of the results the authors state 12 patients were right handed, according  to?

-Could authors elaborate more profoundly why 5Hz for TMS was used and not 10Hz?

-Elaborate more profoundly Classic Laterality Index and Weighted Laterality Index in the methodology with referencing to this is a standardized method.

- raw 253 of the results the authors state 12 patients were right-handed, according to?

-Figure 1 depicts TMS mapping, please explain more deeply the colors (white is no arrest, yellow is speech arrest, and performance errors?) It is not quite understandable what data are from MEG since the MRI is from the TMS mappings. And about the relation of these photos on the laterality of hand.

-Please insert more information on the TMS results regarding mapping of the upper extremity muscles, how resting motor threshold is calculated(RMT), what is the RMT of each subject, and what was the final intensity used for language mapping. The authors are encouraged to insert the table with this information, as well as one table including the results of each language test for MEG, TMS, and Wada to present more profoundly to the readers how language laterality was scored for each method (taking into account each language test per language test. The reader gets only Table 1, without more profound explanations.

-The authors discuss the postoperative results in the Discussion section. It would be recommended that authors include in the Results section also information on the postoperative status of subjects with respect to speech/language testing results versus TMS, Wada, and MEG scoring of the language dominance. This information can also be organized in a table since it is somehow difficult to follow the description (currently placed in the Discussion section).

 

 

Minor

-          The Fig 1 is not entirely visible (the numbers).

Author Response

We thank the reviewers and the editor for their encouraging comments and suggestions to improve the paper. We have made every effort to address the concerns and below we describe the edits made to the manuscript.

 

Reviewer #1:

Wada, and MEG in determining brain language dominance in 12 patients having epilepsy/tumor. The study is interesting, but requires further corrections and explanations:

Major

1.Please elaborate in the Methodology (2.4.1) more profoundly how the synchronization of the presentation of pictures and the stimulus (TMS) application adjusted. Did the authors use external presentation software to trigger the onset of TMS stimulation? What is the TMS stimulation given at the zero time with the picture onset?

 

Response:

Thank you for your valuable feedback. We would like to clarify that each TMS stimulation consists of trains of pulses at 5 Hz, comprising five pulses. In 2012, when we began TMS language mapping, there was a delay of 100 ms to 300 ms between the first pulse of TMS and the onset of the pictures. However, in 2014, Krieg and colleagues (reference # 17 in the manuscript) demonstrated that synchronizing TMS stimulation onset with picture presentation onset enhances the accuracy of TMS language mapping. This synchronization allows TMS to disrupt early activity in language areas, reducing false-negative outcomes and enhancing the specificity of TMS. As a result, in our center after 2014, the picture presentation and onset of TMS stimulation occur simultaneously, without any delay, i.e., the first TMS pulse is applied at picture onset. This synchronization procedure is an integral component of our NexSpeech software (Nexstim, Inc., Atlanta, GA). We have updated the manuscript to incorporate these explanations and considerations in sections “2.4.1. TMS Language Mapping Session”.

 

2.How TMS mapping was standardized per subject, please explain the protocol in language mapping with respect to the brain areas.

 

Response:

Thank you for your comment. TMS language mapping is an individualized test. In each patient, TMS stimulation targeted the superior and middle temporal gyri, starting posteriorly from the supramarginal and angular gyri and extending anteriorly to the extent tolerated by the patient. Subsequently, we stimulated the inferior and middle frontal gyri, encompassing the pars opercularis and pars triangularis, along with premotor and mouth motor regions on both hemispheres. We have made the modifications to the manuscript in section “2.4.1. TMS Language Mapping Session” to include TMS language mapping protocol with respect to the brain areas.

 

3.Elaborate more profoundly on the language tests used in the study for all three methods (TMS, MEG, and Wada) with placing references. Detailed information is missing, for example, how many pictures were finally taken for each subject for mapping, etc.

 

Response:

Thank you for your valuable feedback. With regards to TMS, We would like to clarify that the baseline performance of each patient (without TMS) was evaluated by presenting 50 line drawings of common objects for 1,000 ms, with the interstimulus interval adjusted based on each participant's response time (ranging from 3.5 to 5 s). Patients were instructed to name the objects correctly and as quickly as possible. Any stimuli that were mistakenly named were removed from the stimulus pool, ensuring that all stimuli presented during TMS had corresponding correct baseline recordings. Consequently, the final number of pictures taken for each subject for mapping purposes differed, but it ranged between 20 to 50. We have revised section “2.4.1. TMS Language Mapping Session” to include information about the number of pictures used for TMS language mapping. Appropriate references also were added for all three language methods, i.e., Wada, TMS and MEG.

 

4.In Table 1 of the Results the column “Handedness” states on the hand dominance. Could authors state how the handedness was tested (Edinburgh?), there is no explanation in the Methodology. Please update this information in the Methodology section (and updating also Table 1 for clarification) with the required references.

In the raw 253 of the results the authors state 12 patients were right handed, according  to?

 

Response:

We appreciate your input concerning the assessment of handedness using tests such as Edinburgh inventory. However, it's crucial to clarify that hand dominance data were obtained from patients’ medical records based on patient self-report, and Edinburgh inventory was not applied. Additionally, in row 253 of the “3.1. Patients” section and Table 2, where we indicated that 10 out of 12 patients were right-handed, this information was also derived from patients’ medical records. We have revised section “3.1. Patients” and Table 2 to ensure that our message is clear and prevent any future misinterpretation.

 

5.Could authors elaborate more profoundly why 5Hz for TMS was used and not 10Hz?

 

Response:

Thank you for your comments. For TMS language mapping, a stimulation frequency ranging from 5 to 10 Hz is commonly utilized and widely endorsed (Krieg et al., 2017; reference # 18 in the manuscript). However, employing higher frequencies (such as 10 Hz) often results in side effects such as unwanted jaw muscle contractions, discomfort, and even pain (Tarapore et al., 2016, reference # 19 in the manuscript). Our own experience over 12 years in TMS language mapping has revealed that a frequency of 5 Hz was equally effective and better tolerated by patients, especially younger children. The rationale behind selecting trains of 5 Hz TMS was explained in section “2.4.1. TMS Language Mapping Session”.

 

6.Elaborate more profoundly Classic Laterality Index and Weighted Laterality Index in the methodology with referencing to this is a standardized method.

 

Response:

Thank you for your suggestion. Similar to fMRI (previously described in detail by our group in Schiller et al., 2020; reference # 22 in the manuscript) and MEG (previously described in detail by our group in Rezaie et al., 2020; reference # 23 in the manuscript), TMS-induced speech and language errors can also be utilized for calculating a laterality index (LI). The classic LI is comparable to those employed in fMRI and MEG studies. However, in our experience, incorporating the type of errors through the use of a weighted LI has shown potential to enhance the accuracy of determining language hemispheric dominance (HD) (Rezaie et al., 2020). We have incorporated the rationale for using classic- and weighted LI in determining HD using TMS in Section “2.6.2. TMS Data Analysis”

 

7.Row 253 of the results the authors state 12 patients were right-handed, according to?

 

Response:

Please see our response to Comment # 4.

 

8.Figure 1 depicts TMS mapping, please explain more deeply the colors (white is no arrest, yellow is speech arrest, and performance errors?) It is not quite understandable what data are from MEG since the MRI is from the TMS mappings. And about the relation of these photos on the laterality of hand.

 

Response:
Thank you so much for your valuable feedback. We believe that you are referring to Figure 2. In Figure 2, the T1-weighted MRI image serves as the basis for both TMS and MEG language mapping. The pegs colored gray, white, yellow, and red, projected onto the patient's MRI, represent no error, speech arrest, semantic errors, and performance errors observed during the TMS language mapping session. As detailed in section “2.6.2. TMS Data Analysis”, the classic- and weighted Lateralization Indices (LI)s were calculated using TMS-induced speech and language errors, which include the total count of speech arrests, semantic errors, and performance errors in each hemisphere. Moreover, as outlined in section “2.6.3. MEG Data Analysis”, in MEG language mapping, brain activity sources were modeled as single equivalent current dipoles (ECD). The estimated dipole location corresponding to receptive language mapping (depicted as a Cyan Circle) was then overlaid onto the patient's T1-weighted MRI image. The determination of hemispheric dominance (HD) in MEG language mapping involved comparing the number of acceptable dipoles localized in the left and right hemispheres, alongside evaluating the spatial extent of activation crucial for supporting receptive language function. The patient was found to have right, bilateral, and left HD using classic- and weighted LI with TMS, and MEG, respectively. We have revised the “2.6.2. TMS Data Analysis” and “2.6.3. MEG Data Analysis” sections and Figure 2 caption to ensure that this information is stated correctly.

 

9.Please insert more information on the TMS results regarding mapping of the upper extremity muscles, how resting motor threshold is calculated(RMT), what is the RMT of each subject, and what was the final intensity used for language mapping. The authors are encouraged to insert the table with this information, as well as one table including the results of each language test for MEG, TMS, and Wada to present more profoundly to the readers how language laterality was scored for each method (taking into account each language test per language test. The reader gets only Table 1, without more profound explanations.

 

Response:

Thank you for your suggestion. The resting motor threshold (rMT) for the primary hand motor cortex was mapped at an intensity of 50.17% ± 19.06% (mean ± standard deviation) for the left hemisphere and 45.58% ± 8.11% for the right hemisphere. Trains of TMS pulses were then administered over the temporal and frontal lobes, at intensities of 38.88% ± 4.15% and 36.75% ± 4.90% machine output, respectively. These intensities correspond to approximately 87% and 82% of the rMT in the temporal and frontal areas, respectively. Additionally, Table 1 illustrates hemispheric dominance (HD) as identified by Wada, TMS using classic- and weighted laterality index (LI), and MEG. Moreover, Table 2 presents Wada-based assessments of HD for language compared with HD determined by TMS employing classic- and weighted LI methods, as well as MEG procedures. We have made the modifications to the manuscript in sections 2.4 and 2.4.1. to include information about the intensity used for language mapping.

 

10.The authors discuss the postoperative results in the Discussion section. It would be recommended that authors include in the Results section also information on the postoperative status of subjects with respect to speech/language testing results versus TMS, Wada, and MEG scoring of the language dominance. This information can also be organized in a table since it is somehow difficult to follow the description (currently placed in the Discussion section).

 

Response:

We appreciate your insightful feedback. In response, we have included a new subsection titled "3.3. Post-operative Results" into the results section to cover the findings regarding post-operative language deficits. Additionally, we have expanded Table 1 by adding an extra column to accommodate post-surgery language assessments.

 

Minor

1.The Fig 1 is not entirely visible (the numbers).

Response:

Thank you for your valuable feedback. We updated figure 1 to include the number of patients in each group in Figure 1.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present an interesting study on the comparison of non invasive techniques in the detection of hemispheric dominance. The study is well structured and original. It is a topic often asked by neurosurgeons. 

I have just a few minor concerns that could help the overall already high quality of the manuscript. 

INTRODUCTION

- Despite it is correct to state the reason why the authors decided to design the study, its contribution to the current literature (lines 88-94) should be stated at the end of the discussion or among the conclusions.

- Figure 1 format needs to be updated since some information is missing (cropped from the boxes)

- Lines 107-109: the number of patients included, and their age represent results. 

Author Response

The authors present an interesting study on the comparison of noninvasive techniques in the detection of hemispheric dominance. The study is well structured and original. It is a topic often asked by neurosurgeons. 

I have just a few minor concerns that could help the overall already high quality of the manuscript. 

 

INTRODUCTION

1.Despite it is correct to state the reason why the authors decided to design the study, its contribution to the current literature (lines 88-94) should be stated at the end of the discussion or among the conclusions.

 

Response:

Thank you for your comment. We have changed section “5. Conclusion” to include the contribution of the study.

 

2.Figure 1 format needs to be updated since some information is missing (cropped from the boxes)

 

Response:

Thank you for your valuable feedback. We updated figure 1 to include the number of patients in each group in Figure 1.

 

3.Lines 107-109: the number of patients included, and their age represent results. 

 

Response:

Thank you for your comment. Patients’ age range was edited in lines 107- 109.